L-amphetamine alginate



Sept. 29, 1959 w. T. DoYLE L-AMPHETAMINE ALGINATE A TTRNE Y.

sept. 29, 1959 w. T. DOYL; 2,906,6661

L-AMPHETAMINE ALGINATE Filed March 8, 1957l 3 Sheets-Sheet 3 I I l l INVENTOR. WILL/AM 7. onf

ATTRNEY.

f 2,906,665 y' Patented Slept. 29, 1959 2,906,665 L-AMPHETArnNE' ALGINATE William vvT. Doyle, Livingston, NJ., assignor to Nordson Pharmaceutical Laboratories, Inc., Irvington, NJ., a

corporationv of New York v Application March s, 1957, serial No. 644,927

s claims. (ci. 167-55) The present invention relates to a new molecule of therapeutic importance, namely L-amphetamine alginate. At the present time various-therapeutic agents are known which inhibit appetite and hence are useful in weight reduction regimens. rPhe-most commonly employed agents for anorectic purposesl are rendered less .useful by .reason of the fact that they 'are strong central nervous system stimulants. Their use is accompanied in many instances by objectionable side effects. In many casesit Iis necessary to administer a sedative such as phenobarbital along with anorectic agent in order to vcounteract. the nervous tension sleeplessness and other :Lsymptomscaused by said agents.V In addition, the patient builds up a tolerance to said agents.

The principal problem in obesity is 'not limited lto the :reduction of weight but relates to theloss-gain-loss cycle which in itself causes strain which may bring with it a 'whole vhost of stress-triggered,4 abnormal conditions. Hence what is needed is an anorectic agent which maybe taken over a long period of time to prevent the cyclic gain and loss condition and to assist in estab- 'lishing permanent eating habits to prevent recurrent obesity.

It is a primary object of the present invention to provide a compound which may be employed to effectively suppress the appetite without the usual central nervous system side effects. p Y l Another object is to provide'a novel salt'which has improvedphysical properties over known salts.

Still another object is to provide an anorectic agent which may be employed to assist in establishing permanent dietary habits to prevent recurrent obesity.

A further object is the preparation of the above mentioned new salt in a simple manner whereby a high degree of purity and stability will be assured.

, Ipo-amphetamine alginate achieves all these purposes as well as other objects as will be made more apparent'from a consideration of the following descriptions and claims.

Fig. l is a graphicrepresentation of the infra-red absorption spectra of solid state samples of L-arnphetamine alginate, alginic acid and L-amphetamine sulfate disbursedin KBr. v l

Fig. 2 is a graphic representation ofthe X-ray powder dilraction spectra of L-amphetamine alginate and alginic acid.

Fig. 3 is a graphic representation of the results of a differential thermal analysis between L-amphetarnine alginate and aluminum oxide on the one hand, and alginic acid and aluminum oxide on the other hand, the rate of temperature increase `being 15 C. per minute.

Fig. 4 is a graphic representation of the ultraviolet absorption spectra of L-amphetamine sulfate and L- amphetamine alginate taken at a pH 5 as well as the same compounds taken at a pH l0.

Method 0f preparation L-amphetamine alginate may be formed by the combination of equi-molecular amounts of L-amphetamine and alginic acid, although it may be necessary to add an excess of alginic acid in order to obtain complete conversion of the L-amphetamine to the salt. While, of course, the new salt may be prepared by many methods, a description of the preferred method follows:

L-amphetamine is suspended in 2,500 ml. of distilled water. Alginic acid (800 g. or 5.0 moles, based on a molecular weight ofl76) is added to the L-amphetamine suspension in the form of a r25% paste (800 g. in 3,500 ml. of distilled water), with vigorous stirring, to neutralize the base. The stoichiometn'c amount of alginic acid has been found to be insuicient to neutralize the L-amphetamine, and it may be necessary to add about 176 g. of alginic acid in excess until the solution is neutral to indicator'papen The viscous solution is diluted to ve gallons with-distilled water to permit adequate stirring. i Y

The linal solution, about 90%, is a brownish, opaque, viscous, neutral solution. Y

After the liquid has been prepared, the lluid is sprayed .into a large metalY cone and dehydrated by a current of warmed dry air circulating in the cone. The resulting dry `powder is then removed. The moist vapor is dried almost instantaneously fine powder.

Alginic acid is a polymeric anhydro -D-rnannuronic and the vdried material falls as a acid, having the following chemical structure:

COOH

COOH

Typically the polymeric molecule consists of a chain of about ring units. Methods of its preparation are well known. Cf. U.S. Patent No. 1,814,981 and Seaweeds and Their Uses, by V. J. Chapman, (Pitman Publishing Corporation, 1949), pp. 193 et seq.

The new salt, as described, may be-grouud to any neness required. lt is then ready for compounding into Various forms and preparations for therapeutic use. For availability, it may be incorporated in the customary excipients such asy milk sugar and tale, and made into tablets, each containing 21/2 or 5 milligrams as required. Another convenient and desirable form for oral administration is obtained by incorporating the new salt into the coating of the usual form vof chewing gum. In such a case, the L-amphetamine alginate is incorporated in the outer layer of the gum.

Physical properties L-amphetamine alginate is a slightly bitter and odorless coarse or tine powder and yellowish-white in color. It is readily soluble in water and sparingly soluble or insoluble in most organic solvents. It is'stable under ordinary storage conditions. t

As shown clearly by the Ara-red absorption spectra set forth in Fig. l, L-amphetaminealginate is a distinct salt whose infra-red absorption-lingerprints set it apart from similar salts and substances containing one or more of its constituent moieties. In the solid state then, L- amphetamine alginate is a well characterized substance. The distinctive infra-red spectra illustrated in Fig. l amply demonstrates this.

The conclusion is buttressed by the X-ray powder diffraction spectre set forthvin Fig. 2. The structure of alginic acid is markedly altered in the formation of the amphetamine salt, as is shown by the change in the X-ray pattern, the same being related to the presence of repeated intra-molecular intervals in the polysaccharide chain. Formation of the salt produces changed foci at intervals along the polysaccharide chain and changes the stereo-chemical conformations relative to the unchanged alginic chains. Although not shown, the X-ray spectra of a mixture of alginic acid and liquid amphetamine is identical with that of alginic acid alone and differs markedly from that of L-amphetamine alginate.

Similarly, the differential thermal analysis curve of L-amphetamine, shown in Fig. 3, is markedly different from the corresponding curve of alginic acid. Note particularly the sharp positive spike which occurs in the alginic acid curve in the low 300s which is absent from the L-amphetamine alginate curve. In solution, L-amphetamine alginate shows properties that are similar to those of L-amphetamine sulfate (see Fig. 4). However, note that even here there is a difference. The height of the step at approximately 207 millimicrons is greater in the case of L-amphetamine sulfate. Also, the curve for L-amphetamine sulfate evidences greater irregularities between 250 and 270 millimicrons. Other differences are apparent. Since L-amphetamine is optically active and since alginic acid is likewise optically active, the result in salt is a diastereoisomer.

'Pharmacological and clinical experience Studies done on mice comparing L-amphetamine alginate with L-amphetamine sulfate indicate that the former has a much lower oral toxicity. As an example, a study to determine the 50% lethal dosage of the two compounds used on mice resulted in the following:

L-amphetamine alginate: oral toxicity on mice LD/50=830 mg./kg. L-amphetamine sulfate: oral toxicity on mice LD/50=312 mg./kg.

Another study with a different strain of mice gave the following results:

L-amphetamine alginate=525 (range=85117%) (LD/50 nig/kg.) L-amphetamine sulfate=250 (range=90l10%) (LD/50 mg./kg.) d-Amphetamine sulfate: 50

(range=93-l08%) (LD/50 mg./kg.)

Human clinical evaluations of the'new salt, in which doses of l to 40 mgs. per day were administered, evidenced unusually effective results. It would appear that the salt is relatively long acting and smooth in action. An anorectic result was accomplished Without the central nervous system or cardiovascular system side effects of the other amphetamine compounds. None of the patients complained of loss of sleep. In fact, when live mg. of L-amphetamine alginate was given as late as eight p.m., no interference with sleep was noted although night hunger was diminished. Another unusual finding was the negligible complaints of constipation while losing weight. Patients who were sensitive to other anorectic agents found that they were not sensitive to this salt. Many commented upon the lack of the problem of constipation andsome commented upon the absence of headaches. fact that their appetite was controlled without sleeplessness and without side elects.

Uniformly they were pleasantly surprised by the Therapeutic composition The clinical Work set forth above establishes that the salt may be administered directly without any further active ingredients, as a complete pharmaceutical agent to assist in a weight-reduction regimen by reducing the appetite. As such its effectiveness is heightened by reason of the fact that there is an absence of side effects and the tablets may be .taken at any time of the day without causing restlessness, nervous tension or sleeplessness. However, L-amphetamine alginate may be employed with any other pharmaceutical agents to produce highly useful multi-purpose preparations. Examples of such useful forms follow:

It is obvious that the above are intended generally to alleviate pain in such conditions as dysmenorrhea, headaches, and other conditions.

Of course the above are-merely illustrative and the salt may, of course, be used innumerous other combinations.

It is not desired to be limited except as set forth in the following claims, the vabove description being by way ofillustration ofthe invention, and what is claimed.

1. L-amphetamine alginate.

2. A therapeutic composition comprising as the active agent the L-amphetamine salt of alginic acid.

3. A composition in Vdosage form for controlling the appetite, including not less than 2.1/2 mgs. of L-amphetamine alginate.

References Cited in the le of this patent UNITED STATES PATENTS 2,158,486 Preble May 16, 1939 2,536,168 AGoggin Ian. 2, 1951 2,748,052 Rosner May 29, 1956 OTHER REFERENCES Joun Am. Pharm. Assoc., Prac. Pharm. Ed., December 1955, vol. 16, No. l2, p. 762. 

2. A THERAPEUTIC COMPOSITION COMPRISING AS THE ACTIVE AGENT THEL-AMPHETAMINE SALT OF ALGINIC ACID. 